(28e) Experimental and Simulation Investigation on Application of Metal-Organic Frameworks to Multi-Drugs Carrier

In recent years, combination therapy in which multiple drugs are administered to patients has been used in cancer treatment. This is expected to reduce the dosage of medication due to the synergistic therapeutic effects. However, multiple routes of drug administration used in combination therapy cause side effects and complicated drug resistance mechanisms. To solve this problem, the molecular design of a drug carrier that can include multiple drugs at the same time must be required. Metal-organic frameworks (MOFs) have attracted attention as drug carriers. MOFs are crystalline porous materials synthesized through the self-assembly of metal ions and organic ligands. This study focused on γ-CD-MOFs, which are composed of γ- cyclodextrin (CD) and potassium ions. The CD has a cyclic structure with a hydrophilic outer surface and hydrophobic cavities. Therefore, γ-CD-MOF also has hydrophobic and hydrophilic pores. In addition, γ-CD-MOF has a pore size of 1.7 nm, which is relatively large among MOFs. Its large pore size and low biotoxicity are also considered suitable as a drug carrier. The objective of this study was to evaluate the applicability of γ-CD-MOFs as multiple drug carriers.

In this study, 5-fluorouracil (5FU) and ascorbic acid (ASC) were selected as model hydrophobic and hydrophilic drugs, respectively. The inclusion amounts of each drug in the experiments were measured. Single drug inclusion experiments were performed under various initial drug concentration conditions. The molecular simulations using grand canonical Monte Carlo method (GCMC) were also performed to investigate which of the hydrophilic and hydrophobic pores would encapsulate the drugs. Furthermore, the multiple-drug inclusion ability of γ-CD-MOF was evaluated.

In the single-drug inclusion experiments, both 5FU and ASC were included in γ-CD-MOF with comparable inclusion amounts. The GCMC simulation suggested that 5FU was included in the hydrophobic pore of γ-CD-MOF, followed by the hydrophilic pore. On the other hand, ASC was suggested to be included in hydrophobic and hydrophilic pores at an early phase. The multiple-drug inclusion experiments of 5FU and ASC confirmed that both drugs were simultaneously included in γ-CD-MOF. Comparison with the GCMC simulations suggested that drug-solvent interactions were involved in the actual drug inclusion.